5,5-Diphenylhydantoin, phenytoin, is a commonly used drug for the treatment and management of epilepsy and other types of convulsive states. While phenytoin is widely used for the treatment of these conditions, it has an extremely low solubility and, consequently, low bioavailability. Phenytoin is a high melting, weakly acidic drug exhibiting poor solubility in water. These properties lead to erratic absorption after oral dosing with both the free acid and the sodium salt. See the papers by S. A. Varia et al., Journal of Pharmaceutical Sciences 73(8): 1068-190, August 1984. For parenteral use, sodium phenytoin is formulated in an aqueous alkaline medium of pH 12 containing 40% propylene glycol and 10% ethanol. The parenteral dosage form can be painful if the intravenous injection is rapid and the free acid appears to precipitate at intramuscular injection sites. Emergency use of parenteral phenytoin, namely, in cases of controlling seizures in patients with head injuries, may require the administration of the drug intramuscularly. To be clinically acceptable, intramuscular administration of a drug should cause minimal tissue damage at the injection site. Intramuscular administration of sodium phenytoin has been reported to be painful, probably due to the precipitation of phenytoin. It has also been shown to cause hemorrhage, hematoma and necrosis at the injection site in cats and rabbits.
U.S. Pat. No. 4,260,769 issued Apr. 7, 1981, and the previously noted articles by S. A. Varia et al. in the Journal of Pharmaceutical Sciences, disclose various prodrugs of phenytoin with more desirable physicochemical properties. In particular, patent 4,260,769 and the noted publications disclose the phenytoin prodrug 3-(hydroxymethyl)-5,5diphenylhydantoin disodium phosphate ester which is shown to have physicochemical properties that are suitable for a prodrug of phenytoin for parenteral use. S. A. Varia and V. J. Stella, at pages 1087-1090 in the Journal of Pharmaceutical Sciences, report that the compound did not exhibit any tissue damage after subcutaneous or intramuscular administration and thus, would be a suitable prodrug candidate for intramuscular delivery of phenytoin. However, this prodrug tends to degrade with the subsequent precipitation of phenytoin. Common methods used to delay the precipitation point involve modifying the formulation to contain agents that might solubilize larger quantities of the degradation product. These agents include alcohol, propylene glycol, L-arginine, sodium desoxycholate, polysorbate-80, and various combinations of these compounds.